Hepatocellular carcinoma (HCC) is the second leading cause of cancer death worldwide and in the next decade the incidence of HCC is expected to increase in the U.S. secondary to the increasing number of individuals infected with hepatitis C. HCC often presents at advanced stages and treatment only provides modest benefits in regard to survival. As a result, management of cancer-related symptoms and treatment side effects is critical to maintain health related quality of life (HRQL) and adherence to treatment. In a recent NIH State-of-the-Science Statement, pain, fatigue, and depression were recently reported to be the most common and distressing symptoms of cancer. The concept of symptom clusters has been recently introduced in the field of oncology and the cytokine-immunological theoretical model has been proposed which suggests that cancer-related symptoms, including the pain-fatigue-depression triad, may have a common underlying biological mechanism. We have a unique opportunity to explore this symptom cluster and test the association to related cytokines in a randomized controlled trial (RCT) of an intervention targeting these cancer-related symptoms in people diagnosed with hepatitis B (HBV) and hepatitis C (HCV)-related HCC. We plan to prospectively assess the association between this symptom triad, and related cytokines, in both the standard of care and intervention arm of the RCT. The specific aims of the study are: (1) to prospectively examine the prevalence and association among pain, fatigue, and symptoms of depression and their covariation as a cluster, (2) to prospectively characterize how variation in each individual symptom and/or their covariation as a cluster are associated with changes in immune system parameters (levels of Interleukin [IL]-12, IL-5, IL-6, tumor necrosis factor-1, interferon-3, and NK cell number), and (3) to prospectively determine if changes in symptoms and symptom clusters, and related immune system parameters, are associated with HRQL. The results of this study will provide important information regarding the prevalence and temporal relationship amongst the most common cancer-related symptoms in individuals diagnosed with HBV/HCV-related HCC. The findings of this study may facilitate the development of behavioral and pharmacological interventions to better manage these cancer-related symptoms. The results may also inform researchers studying the role of immunity and disease progression in hepatocellular carcinoma. The aims of the proposed research meet the goals of the NCI by conducting research to understand the biological mechanisms underlying cancer resistance, susceptibility, initiation, regression, progression and recurrence. Our aims also will meet the goals of NCI by increasing our understanding of the ability to measure environmental, behavioral, sociocultural and economic influences that affect the quality of cancer care, survivorship, and health disparities.According to the National Institute of Health (NIH), the three most common and difficult to treat symptoms in people diagnosed with cancer are pain, fatigue, and depression. At this time, health care providers assess and treat these symptoms independently. However, recently the cytokine-immunological model of cancer-related symptoms was proposed. The theory suggests that cancer-related symptoms may have the same common biological cause and therefore other treatment strategies should be developed. We have a unique opportunity to test the cytokine- immunological model as part of a larger study that is testing the efficacy of an intervention to manage cancer-related symptoms. The proposed study (R21) would allow us to assess immune system parameters that may be related to this cancer-related symptom cluster (depression, pain, and fatigue). The larger study will test an intervention using a randomized controlled trial design, which will give us the opportunity to study the relationship between this cancer-related symptom cluster and related immune system markers (e.g., cytokines) with a individuals diagnosed with hepatocellular carcinoma who are either receiving the (1) standard of care (N=111), or (2) the intervention designed to manage cancer-related symptoms (N=111). The primary focus of the proposed study (R21) will be to determine (1) the prevalence of these cancer-related symptoms, (2) the temporal and concurrent relationship between these symptoms, (3) the association between the symptoms and immune system markers (e.g., cytokines, NK cell), and (4) the impact of these symptoms on quality of life. The results of this study will inform researchers who may be interested in developing better behavioral and pharmacological interventions to treat these cancer-related symptoms. The study may also provide additional information regarding the role of immunity in disease progression for individuals who have been diagnosed with hepatoceullar carcinoma.